In models of autoimmune disease in animals and in spontaneous human autoimmune diseases, CD4+ T cells are pathophysiologically involved in disease initiation and progression. Irrespective of the target organ involved, it is likely that similar mechanisms underlie autoimmune disease predisposition and/or induction. One event that seems to be related to the induction of autoimmune disease is loss of "immune regulation". This loss of immune regulation is thought to be a major mechanism underlying most autoimmune diseases. Two of the three projects described within the body of this application (Projects 1 and 2) are directed toward restoring immune regulation in animal models of autoimmune disease through specific immune reconstitution or deviation, or by activating dormant immunoregulatory features of natural regulatory pathways to "prevent" disease initiation or progression. Studies described in Project 3 will use a novel technology of protein arrays screened with autoantibodies to assist in the selection of therapeutic products and as a potential surrogate to success. All three projects described in the body of this grant (as well as the two Innovative Projects) are connected with the overall goal of identifying and then "preventing" induction or progression of the dysregulated autoimmune state. It is hypothesized that autoimmune diseases progress through several (at least two) "checkpoints", an early inflammatory and late phase destructive disease. We believe it might be possible to design ways to identify the two phases and then to develop "common prevention strategies" to arrest disease induction or progression in one or both of these phases. Strategies described in the application suggest that gene therapy or cDNA vaccination might prove effective in the prevention of autoimmune disease induction or perpetuation. If any of these strategies are successful, it is planned to progress to clinical trial application under future funding from this program.